PAREXEL Consulting experts compare regulatory requirements in major drug development markets including the US, EU, Japan and China.

1. © 2018 PAREXEL INTERNATIONAL CORP.
DEVELOPMENT
CONSIDERATIONS:
COMPARING MAJOR
MARKETS INCLUDING US,
EU, JAPAN AND CHINA
Cecil Nick
Vice President, Technical
PAREXEL Consulting
March, 2018

2. © 2018 PAREXEL INTERNATIONAL CORP. / 2
AGENDA
WELCOME • Development considerations: Comparing
major markets including US, EU, Japan and
China
• Hear different approaches to similarity of
quality attributes
• Gain an understanding of navigating different
clinical data requirements and their endpoints
• What are the requirements for choice of
reference product, interchangeability, ethnicity
and need for data from local patients and
conducting global studies?

3. © 2018 PAREXEL INTERNATIONAL CORP. / 3
NAVIGATING THE DIVERGING GLOBAL REGULATIONS
OF BIOSIMILARS
I want to see data in
people from my country
Reference
product
must come
from my
country
If it is OK
in your
country it
is OK
with us
US: This is
not a
biological in
my country!
Do not know
what to do!
Best I do
nothing
I do not care what others
require – we need the data
in drug naïve patients

4. © 2018 PAREXEL INTERNATIONAL CORP. / 4
TOKYO, JAPAN
PLETHORA OF
GUIDELINES

5. © 2018 PAREXEL INTERNATIONAL CORP. / 5
Highly similar
Notwithstanding minor
differences in clinically
inactive components
No clinically meaningful
differences in terms of the
safety, purity, and potency
(amino acid sequence same)
Similarity in terms of
quality, biological activity,
safety and efficacy based
on comprehensive
comparability exercise
Similar, in molecular and
biological terms (amino
acid sequence same)
WHAT IS BIOSIMILARITY?
USEU

6. © 2018 PAREXEL INTERNATIONAL CORP. / 6
The route of administration,
the dosage form, and the
strength of the biological
product are the same as
those of the reference product
Posology and route of
administration same
Deviations as regards
strength, pharmaceutical
form, formulation,
excipients or presentation
require justification
WHAT IS BIOSIMILARITY?
USEU

7. © 2018 PAREXEL INTERNATIONAL CORP. / 7
REFERENCE PRODUCT
•EU and US allow a sponsor to use data derived from animal or
clinical studies comparing a proposed product with a non-U.S.-
licensed product; often 3-way PK bridging is required.
•Equivalent quality, safety and effectiveness to biotechnology
applied drug already approved as a drug with a new active
ingredient in Japan
•China requires that reference product is sourced from the
same manufacturer that supplies the Chinese market
•Most other countries including Japan are satisfied by CMC
bridging data or allow sourcing of reference product from
defined regions

8. © 2018 PAREXEL INTERNATIONAL CORP. / 8
TAIPEI, TAIWAN
THE US VS EU
APPROACH

9. © 2018 PAREXEL INTERNATIONAL CORP. / 9
DEFINITION OF BIOLOGICAL MEDICINE
Annex 1 to Directive 2003/63/EC (3.2.1.1)
produced by or extracted from a biological source and that
needs for its characterisation and the determination of its
quality a combination of physicochemical-biological testing,
together with the production process for its control
Section 351(i), PHSA, 42 U.S.C. § 262(i) a
virus, therapeutic serum, toxin, antitoxin, vaccine, blood,
blood component or derivative, allergenic product,
analogous product, protein (except any chemically
synthesized polypeptide) and arsphenamine or derivative of
arsphenamine (or any other trivalent organic arsenic
compound), applicable to the prevention, treatment, or cure of
a disease or condition of human beings

10. © 2018 PAREXEL INTERNATIONAL CORP. / 10
- 10
-THE EU REGULATORY SYSTEM
Mixed MAA.
Bibliographic
+ Own Data
Similar Biological
Medicinal Product
Comparability
Generic Medicine
(Formerly Essentially
Similar)
Bioequivalence
DIRECTIVE
2001/83/EC
Annex I
Directive 2003/63/EC
Biosimilar data
requirements
267 words
375 Words in EU Directives 7311 Words in US Act in US
Well-Established
Medicinal Use
Bibliographic
Amendment Directive
Dir. 2004/27/EC 30/10/05
Biosimilar
legal concept
108 Words

11. © 2018 PAREXEL INTERNATIONAL CORP. / 11
- 11
-THE US REGULATORY SYSTEM
Hormones (e.g. insulin,
somatropin, FSH transition to
PSA in March 2020
virus, therapeutic serum, toxin, antitoxin,
vaccine, blood, blood component or
derivative, allergenic product, protein
(except any chemically synthesized
polypeptide), or analogous product, or
arsphenamine or derivative of
arsphenamine (or any other trivalent
organic arsenic compound), applicable to
the prevention, treatment, or cure of a
disease or condition of human beings.
375 Words in EU Directives 7311 Words in US Act in US
Synthetic peptides ≤ 100
amino acids, recombinant
peptides ≤ 40 and non
proteins LMW heparin*
remain under FD&C Act
* = Biological in the EU
Section 351 of the Public Health
Service Act (42 U.S.C. 262) amended by
The Biological, Price Competition
& Innovation Act of 2009
Federal Food, Drug,
Cosmetic Act Act) 1938

12. © 2018 PAREXEL INTERNATIONAL CORP. / 12
CHMP BIOSIMILAR GUIDELINES
Similar biological medicinal products
Biosimilar Non-clinical and clinical issues
Biosimilar Quality issues
Biosimilar recombinant granulocyte-colony stimulating factor
Biosimilar low-molecular-weight heparins (not biosimilar in US)
Biosimilar recombinant human insulin and insulin analogues
Biosimilar interferon beta
Biosimilar monoclonal antibodies: non-clinical and clinical issues
Biosimilar erythropoietins
Biosimilar recombinant follicle-stimulating hormone
Biosimilar somatropin
Orange = in US will be biosimilar in 2020

13. © 2018 PAREXEL INTERNATIONAL CORP. / 13
FDA BIOSIMILAR GUIDELINES
NO PRODUCT SPECIFIC GUIDELINES
Formal Meetings Final 11/17/15
Scientific Considerations Final 04/28/15
Quality Considerations Final 04/28/15
Clinical Pharmacology Data Final 05/13/14
Reference Product Exclusivity Draft 08/04/14
Biosimilars: Additional Questions
and Answers
Draft 05/12/15
Biosimilars: Questions and Answers Final 04/28/15
Interchangeability Draft 01/17/17
Statistical Approaches to Evaluate
Analytical Similarity
Draft 9/21/17

14. © 2018 PAREXEL INTERNATIONAL CORP. / 14
NEW US BIOSIMILAR LEGISLATION
BIOLOGICAL, PRICE COMPETITION AND INNOVATION ACT OF 2009
• 12 years market exclusivity for the innovator product
“Modification of structure” allows further 12 years provided
gives added advantage
• One year of market exclusivity for the first interchangeable
biosimilar product
• -- No such concept in EU
• Confidential exchanges of detailed substantive patent
contentions between biosimilar applicant and innovator BLA
holder
- No such concept in EU
• Nomenclature
- US: INN/USAN + random 4 letter suffix (unless
IC?)
- EU: INN – inverted black triangle indicates special
ADE reporting

15. © 2018 PAREXEL INTERNATIONAL CORP. / 15
SUBSTANTIVE DIFFERENCES US VS. EU REGULATIONS
US EU
Regulations Extensive 7311 Words in US Act Light 375 Words in EU
Directives supported by
extensive guidance docs
Biosimilar rDNA Peptide >25 aa/Protein rDNA Peptide/Protein;
complex carbohydrates
Originator
Exclusivity
12 yrs market exclusivity for
innovator “Modification of structure”
alows further 12 years provided
added advantage.
EU is 10 years basic but
new indications and
paediatric development
allows up to 12 years.
Interchange-
ability
1 yr market exclusivity for 1st
interchangeable biosimilar
No such concept
Patent dance Confidential exchanges of detailed
substantive patent contentions
between biosimilar applicant and
innovator
No such concept
Nomenclature INN/USAN + random 4 letter suffix
(IC?)
lNN – inverted black
triangle indicates special
ADE reporting

16. © 2018 PAREXEL INTERNATIONAL CORP. / 16
CMC REQUIREMENTS: US VS. EU
US EU
Approach Tiered statistical
approach
Less defined/more
flexible
Number of Batches Often >15 RP and
>10 BS
Less as no statistical
equivalence
Testing requirements Similar
Acceptable differences Differences need to be justified

17. © 2018 PAREXEL INTERNATIONAL CORP. / 17
CMC DATA: POINTS TO CONSIDER
• Variability of reference product
• Batch-to-batch
• Process change
Test many batches over extended period
• Testing Program
• State-of-the-art
• Orthognal
• Reliable - accurate, precise and robust
• Acceptability of differences
• Understand impact of differences and justify
• Biological activity needs to be closely matched
FDA require statistically driven approach whereas CHMP do not
17

18. © 2018 PAREXEL INTERNATIONAL CORP. / 18
IMPACT OF CQA DIFFERENCES
Efficacy PK
Immunogenicity Safety
Theoretical
General literature
Literature on reference product
Studies on biosimilar
Mass contribution

19. © 2018 PAREXEL INTERNATIONAL CORP. / 19
US: CRITICALITY ASSESSMENT OF QUALITY
ATTRIBUTES (CQA)
Tier 1
• 2/3 representative CQAs that
directly impact safety/potency
• e.g. Rituximab = ADCC &
CDC; Infliximab = anti-TNF
binding & reverse signalling
Tier 2
• Other CQAs that impact safety/
potency
• e.g. non/low activity impurities
Tier 3
• Little or no impact on safety
and/or potency e.g. fully active
variants
These required to fall within +/- 1.5
SD for results from multiple
reference product batches. It may
be possible to justify broader limits.
Quality range approach generally
±3SD based on multiple reference
product batches.
Descriptive
Graphical display

20. © 2018 PAREXEL INTERNATIONAL CORP. / 20
•Defined as separate
category in BPCI
• Very high hurdle
• “same clinical result in
any given patient;” and
risk of alternating or
switching no greater
than use of reference
product
• Not regulatory concept
• Decision at national level
• Initially general view
biosimilars not as
interchangeable but view
shifting
WHAT IS BIOSIMILARITY?
US EU

21. © 2018 PAREXEL INTERNATIONAL CORP. / 21
DEMONSTRATING INTERCHANGEABILITY MEAN?
• How much data?
• Molecular complexity
• Level of similarity
• Knowledge of impact of differences
• Known risks e.g. immune related reactions
• Interchangeability study
• Switch study generally required (unless e.g. single administration)
– ------------------------------ US Reference-------------------------------- (>6 mths)
– US Reference------Biosimilar-------US Reference–------Biosimilar (>6 mths)
• 1 Endpoint: AUCτ and Cmax (steady state after last switch ; ensure reference washed out)
– Margin 80 – 125% (Sample Size ~200)
• 2 Endpoint: PD, Immunogenicity, Safety, Efficacy.

22. © 2018 PAREXEL INTERNATIONAL CORP. / 23
• Take into consideration
- Any particular safety or
effectiveness concerns
associated reference product or
putative interchangeable
product
- The specific condition of use
and patient population, and
patient exposure in the
interchangeability development
program.
• Post marketing safety monitoring
for an interchangeable product
should also have adequate
pharmacovigilance mechanisms
in place
DEMONSTRATING
INTERCHANGEABILITY?
POST -MARKETING SAFETY
MONITORING
CONSIDERATIONS

23. © 2018 PAREXEL INTERNATIONAL CORP. / 24
ACCEPTABILITY OF DIFFERENCES: RECENT US
EXPERIENCE
• Differences in formulation which had minor impact on PK accepted 1
• 1 new peak for ABP215 only = sequence variant due to a point
mutation Ser121 to Ala stable and <1% not part of the complementarity
determining region - ala will not perturb structure because switch from
1 small amino acid to another2
• Lower level of misformed S-S bonds increased in vitro potency but
justified based on S-S reform correctly in vivo3
• Lower aggregate levels for ABP215 Amgen’s Mvasi (bevacizumab)
HMWS 0.3% vs 0.46/7% 4
• Charge variants: ASN30>in US RMP; 2 additional peaks in MYL-
1401O related to oxidation at Met 255 and Asn30 deamidation 4
• 1 Sandoz Zarxio ODAC
• 2 BLA 761028: ABP215, biosimilar to US-Avastin, ODAC Briefing Document 13 July 2017
• 3 Sandoz etanercept (Arthritis Adcom Transcript 15/7/16)
• 4 BLA 761074 ODAC Briefing Document MYL-1401O, biosimilar to US-Herceptin 13 July 2017

24. © 2018 PAREXEL INTERNATIONAL CORP. / 25
ACCEPTABILITY OF DIFFERENCES: RECENT US
EXPERIENCE
• Slight change in levels of glycans
–Do not preclude a determination of high similarity (Amgen’s
adalimumab1
–Bevacizumab diff Mann5/6 and sialic acid unlikely to have a clinical
impact as bevacizumab has predominantly soluble target 2
• Differences in ADCC accepted
– Not considered a relevant MoA3
–Greater than 90 percent of lots of the proposed biosimilar are still
within the quality range of the reference product 4
1 FDA Arthritis Adcom Slides 14July16
2 4 BLA 761074 ODAC BD MYL-1401O, biosimilar to US-Herceptin 13 Jul 2017
3 Sandoz etanercept: Arthritis Adcom transcript 15July16
4 Celltrion infliximab: Arthritis Adcom transcript 9Feb16.

25. © 2018 PAREXEL INTERNATIONAL CORP. / 26
NON CLINICAL
• Need for in vivo data based on tiered risk based approach
• Generally require only in vitro data
• Need for in vivo data often questioned
• In vitro data generally not considered in non clinical section
• In vivo data required if first in humans studies to be done in US
• Existence of clinical data may eliminate need for non clinical data
Some other jurisdictions require more comprehensive non clinical data e.g. India,
Japan, China.

26. © 2018 PAREXEL INTERNATIONAL CORP. / 27
PK/PD
• Following much debate in early days HV studies preferred
globally
• Ctrough data from patients also required
• CHMP will compare with historic data
• 3-way PK bridge: Test vs. EU RP vs. US. RP
– FDA: 3-way PK equivalence study waived in favour of separate 2-way studies
on the basis that two studies performed in same Unit using same methods and
similar protocol.
– CHMP have accepted CMC bridge without 3-way PK

27. © 2018 PAREXEL INTERNATIONAL CORP. / 28
PD CONSIDERATIONS
Response
Dose
Steep part
of dose
response
curve May need
to test at
several
doses
Endpoint may not need to be validated
but must be relevant + show clear
dose/concentration response
relationship.
Occasionally may replace clinical trial

28. © 2018 PAREXEL INTERNATIONAL CORP. / 29
EARLY US APPROACH: SURROGATE CLINICAL
ENDPOINTS
• Coherus PegFilgrastim
• Entire program in healthy volunteers
• Single dose PK/PD study
• Immunogenicity – two doses in ~300 patients
• FDA did not request additional clinical study to be
performed in oncology patients
GABI OnLine 11/11/2016: FDA accepts application for pegfilgrastim biosimilar from
Coherus; CliniTrials.gov
- 29 -

29. © 2018 PAREXEL INTERNATIONAL CORP. / 30
HOW MUCH CLINICAL
DATA?
NON CLINICAL AND CLINICAL
GUIDELINE
(EMEA/CHMP/BMWP/42832/05)
• Usually comparative clinical trials
required
• Safety data must be sufficient
• Clinical comparability margins should
be pre-specified and justified,
primarily on clinical grounds
• Assay sensitivity (see ICH topic E10)
has to be ensured
• If a clinical comparability trial design is
not feasible, other designs should
be explored and their use
discussed with the competent
authorities
• Clinical safety of similar biological
medicinal products must be
monitored closely on an ongoing basis

30. © 2018 PAREXEL INTERNATIONAL CORP. / 31
CLINICAL TRIAL DATA: FDA VS. EU
US EU
Trial Population Most sensitive – but views on this can
differ
Endpoints Views may differ
Equivalence
margin
Risk Ratio Proportions
Preserve >50%
effect
> Putative placebo
effect
90% CI 95%CI
Switching May be required Discouraged
Study duration 12 months 12 months

31. © 2018 PAREXEL INTERNATIONAL CORP. / 32
IMMUNOGENCITY
• Immunogenicity usually secondary endpoint
• Sometimes FDA will require a formal immunogenicity
study
• “a one-sided design will ordinarily be adequate to
compare clinical immunogenicity of the proposed
product and reference product.”
• Setting margin can be challenging as one cannot
rely on historical data – need to consider adaptive
trials
Kozlowski et. al. “the FDA will evaluate
immunogenicity in a risk-based manner.”

32. © 2018 PAREXEL INTERNATIONAL CORP. / 33
IMMUNOGENCITY
Coherus PegFilgrastim: FDA rejected BLA requesting a ‘re-analysis
of a subset of subject samples with a revised immunogenicity assay’
GABI online 07/07/2017: FDA rejects pegfilgrastim biosimilar from Coherus

33. © 2018 PAREXEL INTERNATIONAL CORP. / 34
EXTRAPOLATION TO OTHER USES?
• Extrapolation accepted in guidelines in EU, USA, Canada and Japan
• Requires adequate justification
• Immunomodulator and anticancer (cytotoxic) antibody, extrapolation
more challenging (CHMP Guidance)
• Antibody-dependent cytotoxicity (ADCC) appears to be more
important in some indications than in others
• Should extrapolate immunogenicity findings from sensitive to non
sensitive populations: e.g. not immunosuppressed and more liable
to produce antibody response
• In contrast to EU, FDA require pediatric plan with biosimilar
application unless interchangeable status granted

34. © 2018 PAREXEL INTERNATIONAL CORP. / 35
NEED FOR DATA IN LOCAL POPULATION
• US: EU patients not essential but justify studied population
representative of EU
• EU: EU patients not essential but justify studied population
representative of EU
• India: Variable, figure 100 Indian patients often cited
• Russia: Variable, often OK to include Russian patients in trial or perform
small separate study in Russia
• Mexico: Request some local patients to be included
• Japan: Require exposure of some Japanese subjects
• China: Full program in China no longer required need to justify
extrapolation from non Chinese population and likely need some patients
ex China

35. © 2018 PAREXEL INTERNATIONAL CORP. / 36
JAPAN
• Need ethno-bridging data
• PK/PD study in Japanese patients (suitability of HVs
should be discussed with MPA)
• OR Include adequate Japanese patients in global
study
• OR Include Japanese subjects in PK equivalence
trial
• Provide CMC bridge to Japanese reference product and
reference product used in the trial
• US/EU directed program may be suitable but need to
discuss with MPA – differences in dosage, ethnic
response, approved indication could complicate bridging.

36. © 2018 PAREXEL INTERNATIONAL CORP. / 37
CHINA
Major Changes
• Lower regulatory hurdle, much faster approval timeline
• New drug definition to encourage company to put China
into the first round of global registration by favoring re-
imbursement
• Faster & Cheaper Clinical development in China
• Aim to align with ICH requirements; in parallel will also
take China specific requirements into consideration.
• CMC: China pharmacopoeia & guidance; “establish
condition”
• Chinese safety & efficacy profile must be well
address by taking ICH E5&17 into consideration
• Guidelines for biosimilars such as bevacizumab

37. © 2018 PAREXEL INTERNATIONAL CORP. / 38
• “Foreign clinical data” can be
conditionally accepted to
support China registration:
• Efficacy and safety are well
addressed with foreign data
and expanded to Chinese
• Ethnic sensitivity should be
well addressed
• All the sites comply with ICH
GCP requirements and ready
for CFDI
• China local clinical data must
generate for China
registration and “foreign
clinical data” can only use for
reference
CHINA: ACCEPTANCE OF FOREIGN CLINICAL DATA
AFTER CHANGEBEFORE CHANGE
More science based negotiation
with CFDA could be expected!
Underline means it can be implemented after
new DRR is in force.

38. © 2018 PAREXEL INTERNATIONAL CORP. / 39
LONDON, U.K.
GLOBAL
DEVEOPMENT
CONSIDERATIONS

39. © 2018 PAREXEL INTERNATIONAL CORP. / 40
REPRESENTATIVE GLOBAL BIOSIMILAR PROGRAM –
PLAN AHEAD
3-way PK study with BS vs. EU RMP vs. US RMP
Separate ethnicity trials in Chinese,
patients??
Global patient study
USA
EU
RoW
India,
Russia
HV PK/PD bridging study in Japan
Global Efficacy Study vs. EU RMP
1 or 2 year Safety Extension
China,
Japan
PK/PD study

40. © 2018 PAREXEL INTERNATIONAL CORP. / 41
CONCLUSIONS
• EU and US apply very definitions to “Biological Medicine”
• EU and US regulatory systems very different
• 375 Words in EU Directives vs 7311 Words in US Act
• EU more reliant on guidelines
• EU decisions based on consensus; FDA based on Division opininion
• US regulations introduce concepts novel to EU
• Patent dance
• Interchangeability
• Despite Efforts towards harmonisation FDA and CHMP can take
take different stances
• Important to discuss requirements with Agencies at early stage

41. © 2018 PAREXEL INTERNATIONAL CORP. / 42
THANK YOU
© 2018 PAREXEL INTERNATIONAL CORP. / 42